Dexmedetomidine improves mitophagy and pyroptosis through the ALKBH5/FUNDC1 axis during epidural-related maternal fever

Purpose: Epidural analgesia has emerged as a commonly used method for relieving labor pain. However, epidural-related maternal fever (ERMF) is characterized by a high occurrence rate and can have detrimental consequences for the well-being of both the mother and the fetus. This study aimed to investigate the functional role and underlying mechanism of dexmedetomidine (DEX) in ERMF.

Materials and methods: Ropivacaine (ROP)-induced human umbilical vein endothelial cells (HUVECs) were treated with DEX and/or transfected with ALKBH5 or FUNDC1 overexpression plasmid. qPCR and Western blot were adopted for Mitophagy and Pyroptosis marker protein detection. Autophagosomes were observed through electron microscopy, Caspase-1/PI double-positive cells were determined using flow cytometry. Inflammation-related factors were quantified using ELISA. The N⁶-methyladenosine (m⁶A) modification of FUNDC1 mRNA was examined using methylated RNA immunoprecipitation (MeRIP) and the binding between ALKBH5 and FUNDC1 mRNA was confirmed by RNA immunoprecipitation (RIP).

Results: In ROP-induced HUVECs, there was a significant upregulation in ALKBH5 and FUNDC1, resulting in a notable increase in inflammation, Pyroptosis, and Mitophagy. The administration of DEX demonstrated the ability to alleviate ROP-induced Pyroptosis and promote protective Mitophagy. Interestingly, DEX treatment significantly reduced the interaction between ALKBH5 and FUNDC1 mRNA, while simultaneously increasing the m⁶A level of FUNDC1 mRNA in ROP-treated cells. Moreover, the overexpression of FUNDC1 partially reversed the effects of ALKBH5 overexpression on Mitophagy and Pyroptosis in HUVECs.

Conclusions: DEX can promote Mitophagy and inhibit Pyroptosis through the ALKBH5/FUNDC1 axis in ERMF, indicating its potential as a therapeutic strategy for clinical ERMF treatment.

ALKBH5; Dexmedetomidine; Epidural-related maternal fever; FUNDC1; pyroptosis.